In the renewal period this Project will investigate the mechanisms of bone loss through the paradigm of primary hyperparathyroidism in estrogen deficient, postmenopausal subjects. The studies are based upon observations we have made in the previous funding period. Cancellous bone is preserved while cortical bone is at risk. Postoperatively, there is a pervasive gain in bone mass at all sites, irrespective of their composition type. In the renewal period, these central observations will be pursued further with attention to four specific areas. We will continue to monitor the course and reversibility of the hyperparathyroid process in postmenopausal women. These studies will include a longitudinal analysis utilizing serum and urinary biochemical determinations, densitometry, and histomorphometry. Second, we have identified subgroups of postmenopausal women who may be at risk for deleterious outcomes. Three groups have been identified: women who present in an anomalous fashion with reduced cancellous bone content perimenopausal women whose hyperparathyroidism is potentially adversely influenced by the onset of estrogen deficiency; and women who are deficient in vitamin D. A third area of inquiry is a characterization of biochemical mediators of parathyroid hormone action as they related to other indices of disease activity, to pathophysiological consequences, and to postoperative recovery. The fourth area to be studied in Project 4 is the histomorphometric features of bone in primary hyperparathyroidism. We plan to reconstruct the dynamics of the bone remodeling unit in primary hyperparathyroidism. We plan to reconstruct the dynamics of the bone remodeling unit in primary hyperparathyroidism. We will also be assessing the histomorphometric changes that occur after patients undergo successful parathyroid surgery in an attempt to understand the counter-intuitive robust increase in bone mass that follows. Bone biopsy samples will be obtained before and one-year postoperatively. Along with detailed biochemical and densitometric studies that will be conducted over this same period, we should be uniquely poised to gain more complete understanding of the anabolic and catabolic properties of parathyroid hormone. The project melds with the overall aim of the SCOR in that it should lead to additional insight into mechanisms of bone loss in general among postmenopausal women and how these mechanisms, presumable due to estrogen deficiency, are influenced by parathyroid hormone.